Structure–function relationships of citrus limonoids on p38 MAP kinase activity in human aortic smooth muscle cells

Limonoids, abundantly present in citrus fruits, have potential role in reducing risk of different type of cancer. In the present study, we hypothesized that seven structurally different limonoids would involve in inflammatory pathway via modulating p38 MAP kinase activity at various extent in vascular smooth muscle cells. Results demonstrated that the different functional groups containing limonoids had differential effects on the p38 MAP kinase activity in human aortic smooth muscle cells. Among seven limonoids, nomilin exhibited the highest (38%) inhibition of p38 MAP kinase activity, followed by limonin (19%), deacetyl nomilin (19%), and defuran nomilin (17%). While defuran limonin and methyl nomilinate showed no significant decrease in p38 MAP kinase activity, obacunone significantly increased the p38 MAP kinase activity by 38%. Furthermore, TNF-α induced p38 MAP kinase activity in the smooth muscle cells was completely inhibited by nomilin. Thus our data provide the first evidence that nomilin is the potent natural inhibitor for p38 MAP kinase activity in human aortic smooth muscle cells. These data also suggest that a seven-membered A ring with acetoxy group, present in nomilin, seems to be essential for its inhibitory activity on p38 MAP kinase.